Blood cell development depends on precisely controlled gene expression programs that govern the commitment and maturation of progenitor cells along specific lineages. In addition to transcription factors that regulate gene expression during the course of lineage commitment, intact cell cycle control mechanisms are critical to normal blood cell maturation. In a mouse knock-in model developed to study the physiologic consequences of dysregulated cyclin E, a protein that regulates S-phase entry, we found abnormal red blood cell maturation, with increased proliferation, apoptosis, and dysplastic morphologies in erythroid progenitors. These features are characteristics of hematopoietic cells of patients with early-stage myelodysplastic syndromes (MDS). We hypothesize that proper regulation of cyclin E is critical during normal hematopoiesis and that deregulated cell cycle controls contribute to the pathogenesis of blood diseases such as MDS and leukemia. The Fbw7 ubiquitin ligase is a major regulator of cyclin E activity and also controls the abundance of other important oncogenic proteins involved in cell growth and proliferation. Fbw7 loss-of-function mutations are found in acute leukemias, and mutations in signaling pathways associated with myelodysplasia and leukemias can impair Fbw7- mediated cyclin E degradation. We recently found that the p53 tumor suppressor is activated in erythroid progenitor cells in a DNA damage-type response to impaired Fbw7-mediated cyclin E degradation. In the proposed studies comprising Aim 1, we will first define how high cyclin E and the molecular response it evokes alters normal erythroid cell maturation. MDS is a heterogeneous group of blood diseases caused by hematopoietic stem cell defects. In studies proposed in Aim 2, we will test the hypothesis that Fbw7-mediated cyclin E regulation critically maintains normal hematopoietic stem cell function. Mutations in p53 are found in advanced stage MDS, which is associated with progression to frank leukemia. In Aim 3, we will test the hypothesis that compromised p53 function cooperates with dysregulated cyclin E in hematopoietic progenitors to induce neoplasia in vivo. We will develop mouse marrow transplantation models to test this hypothesis by disabling p53 function in cyclin E knock-in hematopoietic cells, either directly by allelic deletion or indirectly via dysregulated expression of another oncogenic substrate of Fbw7, c-Jun.